7082 results for "canc*"

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• CSER: Exome Sequencing in Diverse Populations in Colorado and Oregon/CHARM Cancer Health Assessments Reaching Many

  The CHARM (Cancer Health Assessment Reaching Many) study, part of the Clinical Sequencing Evidence-Generating Research (CS.ER2) effort, aimed to assess the utility of clinical exome sequencing and how it affects care in diverse populations. The study population included adults at risk for hereditary cancer syndromes. The primary objective was the implementation of a hereditary cancer risk assessment program in healthy 18-49 year-olds in primary care settings within a vertically integrated health delivery system (Kaiser Permanente) and a federal qualified health center (Denver Health). The investigators aimed to assess clinical exome sequencing implementation and interpretation, as well as tailored interactions for low health literacy including a contextualized consent process, and a modified approach to results disclosure and genetic counseling. The investigators were also assessing the clinical utility (healthcare utilization and adherence to recommended care) and personal utility of primary and additional results from clinical exome sequencing, and evaluate the ethical and policy implications of considering personal utility of genomic information decisions for health care coverage.Sequencing and analysis for CHARM was conducted at the Northwest Clinical Genomics Laboratory, University of Washington, Seattle (https://nwgc.gs.washington.edu/).

  Study phs002111

• Genomic and Immune Profiling of Breast Cancer Brain Metastases

  Previous work has shown that breast cancer brain metastases (BCBrM) can have unique molecular profiles compared to extracranial tumors (ECTs), resulting in some patients demonstrating subtype switching between primary/extracranial tumors and brain metastases. Description of the biology of BCBrM and associations between biological features and clinical outcomes, particularly between molecular intrinsic subtypes, will facilitate the design of rational therapies for patients with BCBrM. To better characterize the molecular profiles of BCBrM, we conducted whole exome sequencing (WES) and total RNA sequencing (RNA-Seq) on BCBrM tissues, regardless of clinical or molecular subtype, obtained from a cohort of 42 patients from Duke University Medical Center. This cohort adds valuable patient samples to the field and enables strengthened investigation of somatic mutations, copy number alterations, gene expression profiles, and immune populations within and between BCBrM patients and other similar cohorts. The Duke BCBrM cohort includes clinical and molecular annotation of the 42 patient specimens and their associated WES and RNA-Seq data. Clinical and molecular (PAM50) intrinsic subtypes in ECTs and brain metastases were largely concordant within patients. There were observed differences in intrinsic subtype calls between frozen and FFPE specimens of the same tissue, with discordance mostly observed with LumB calls. Copy number alterations in chromosomal regions included clinically relevant genes, and somatic alterations were largely conserved within patients across matched samples, with few genes, including TP53, being recurrently altered in the majority of patient specimens. In matched FFPE brain metastasis and ECT samples, we observed differentially expressed genes and pathways that had increased or decreased expression in brain metastasis, including in oxidative phosphorylation and DNA repair. Survival outcomes for patients differed by intrinsic molecular subtypes, with some association between expression of select gene pathways and survival. Data available through dbGaP will be the sequencing data and sample attributes from BCBrM tissues obtained from 42 patients from Duke University Medical Center.

  Study phs003673

• MSK SPECTRUM - SPatiotemporal Evolution of Cancer Traced Using Multimodalities

  MSK SPECTRUM is a multi-modal, interdisciplinary prospective study of spatiotemporal determinants of high-grade serous ovarian cancer (HGSOC) evolution, treatment and response. Accounting for ~80% of ovarian cancers, HGSOC is the most lethal gynecological malignancy and is a cancer of major unmet clinical need. Challenges in disease management relate to several unresolved questions about disease biology and diagnostic modalities. Prospective longitudinal collection of tissues and blood from laparoscopic biopsies and debulking surgeries enable multi-modal molecular measurements. The program brings together formidable expertise at Memorial Sloan Kettering Cancer Center (MSKCC) across the disciplines of high-resolution genomics and computer science, radiology and radiomics, surgery, tissue banking and sample preparation, medical oncology, immuno-oncology and high-resolution tissue profiling to generate a comprehensive and integrative dataset that will allow us to address the following major aims: i) characterize malignant and immune diversity at diagnosis, ii) survey the co-evolution of malignant cells and the immune response, and iii) stratify patients on standard-of-care and investigational compounds based on their genomic and transcriptomic signatures and changes to relevant genes (TP53, CCNE1, BRCA1/2, CDK12). The goal is to create a framework to utilize integrated multi-modal data as a route to advanced diagnostics and to ultimately establish a proof-of-concept for integrated diagnostics.

  Study phs002857

• Coding and regulatory somatic profiling of triple-negative breast cancer in Sub-Saharan African patients

  The burden of triple-negative breast cancer (TNBC) may be shaped by genetic factors, particularly inherited and somatic mutation profiles. However, data on this topic remain limited, especially for the African continent, where a higher TNBC incidence is observed. In the age of precision medicine, cataloguing TNBC diversity in African patients becomes imperative. We performed whole exome sequencing, including untranslated regions, on 30 samples from Angola and Cape Verde, which allowed to ascertain on potential regulatory mutations in TNBC for the first time. A high somatic burden was observed for the African cohort, with 86% of variants being so far unreported. Recurring to predictive functional algorithms, 17% of the somatic single nucleotide variants were predicted to be deleterious at the protein level, and 20% overlapped with candidate cis-regulatory elements controlling gene expression. Several of these somatic functionally-impactful mutations and copy number variation (mainly in 1q, 8q, 6 and 10p) occur in known BC- and all cancer-driver genes, enriched for several cancer mechanisms, including response to radiation and related DNA repair mechanisms. TP53 is the top of these known BC-driver genes, but our results identified possible novel TNBC driver genes that may play a main role in the African context, as TTN, CEACAM7, DEFB132, COPZ2 and GAS1. These findings emphasize the need to expand cancer omics screenings across the African continent, the region of the globe with highest genomic diversity, accelerating the discovery of new somatic mutations and cancer-related pathways.

  Study EGAS50000001013

• WES in Angolan and Cape Verdean triple-negative breast cancer samples

  WES (using the SureSelect Human All Exon V5 + UTRs target enrichment kit) in 23 Angolan and 7 Cape Verdean triple-negative breast cancer samples

  Dataset EGAD50000001482

• WES in Angolan and Cape Verdean triple-negative breast cancer samples

  WES in 23 Angolan and 7 Cape Verdean triple-negative breast cancer samples

  Dac EGAC50000000486

• Liquid Biopsy Detection of Tumor-specific Structural Variants in High Grade Serous Ovarian Cancer

  WGS Liquid Biopsy. Recurrence is frequent for most patients with high grade serous ovarian cancer (HGSOC), even after effective chemotherapy induced remission. However, after achievement of complete clinical response, the minimal residual disease is often insufficient for genomic analysis. Therefore, methods to interrogate the clonal composition and molecular properties of minimal residual disease are needed to better understand the mechanisms of HGSOC relapse. To address this unmet need, we developed and validated a novel cfDNA-based approach for tracking disease burden using NGS-informed tumor specific structural variants (SVs). Methods: The optimization of the methodology was first performed using synthetic cfDNA generated by ultrasonication of gDNA from ovarian cancer cell lines. Following the optimized workflow, whole genome sequencing of multisite biopsies from pre-treatment HGSOC patients were performed and high confidence SVs were called by consensus of multiple published SV callers. Real-time PCR and digital droplet PCR (ddPCR) were used for assays development.

  Study EGAS50000001044

• Liquid Biopsy High Grade Serous Ovarian Cancer WGS

  Liquid Biopsy High Grade Serous Ovarian Cancer WGS.

  Dataset EGAD50000001520

• Localised colon cancer WES study contaning WBCs, tissue and plasma samples at different time points

  Decision-making based on circulating tumor DNA (ctDNA) status following curative-intent surgery in stage II-III colon cancer (CC) is where the strongest clinical evidence lies. Commercial or academic assays are predominantly used to detect ctDNA, aiming to reveal minimal residual disease (MRD) and identify patients at high risk of recurrence. However, while current tests demonstrate exceptional specificity in detecting MRD among patients who later experience recurrence, their sensitivity is notably limited, particularly immediately after surgery when decisions regarding ACT are crucial. Additionally, up to 70% of patients with stage II-III colon cancer fail to clear ctDNA after standard adjuvant treatment (ACT) and subsequently experience recurrence. In this study, we performed whole exome sequencing (WES) of ctDNA at different timepoints in relapsed CC patients using two independent cohorts, alongside transcriptomic and proteomic analyses of metastases to gain a deeper understanding of progression mechanisms. An assay based on a tumor-agnostic approach from WES could enhance sensitivity in detecting MRD disease compared to current assays. Immune evasion appears to be the primary driver of progression in the localized CC setting, facilitated by a functional mutational burden at relapse. This suggests that immunotherapy could extend its efficacy to patients with microsatellite stability, broadening treatment options. Moreover, organoid modeling affirms the promising potential of targeted therapy to surpass conventional treatments in eradicating MRD.

  Study EGAS50000000204

• Assessing gene expression profiling from FFPE Patient Samples: A Comparison of Two Library Preparation Approaches and Recommendations

  Next-Generation Sequencing (NGS) has transformed cancer research and clinical practice, with Whole Exome Sequencing (WES) driving advances in mutational profiling and personalized oncology. Yet, transcriptomic signatures remain essential for understanding disease mechanisms, including therapy resistance pathways. RNA sequencing (RNA-seq), however, faces unique challenges when dealing with low-input or degraded RNA, as often found in archival formalin-fixed paraffin-embedded (FFPE) tissues. Although previous studies have compared library preparation protocols, rapidly evolving technologies call for updated evaluations. Here, we present a direct comparison of two FFPE-compatible stranded RNA-seq library preparation kits: TaKaRa™ SMARTer® Stranded Total RNA-Seq Kit v2 (Kit A) and Illumina Stranded Total RNA Prep Ligation with Ribo-Zero Plus (Kit B). Both kits generated high-quality RNA-seq data, yet important differences emerged. Notably, Kit A achieved comparable gene expression quantification to Kit B while requiring 20-fold less RNA input, a crucial advantage for limited samples, albeit with increased sequencing depth. We critically discuss these results in relation to RNA availability, technical performance, cost-effectiveness, processing time, and automation potential, offering practical guidance for selecting optimal RNA-seq strategies in clinical and translational research settings

  Study EGAS50000001066

• High volume culture initiating in vitro evolution in neuroblastoma cell lines

  Despite the advent of advanced molecular prognostic tools, it is still difficult to predict the course of disease for cancer patients at the individual level. This lack of predictability is also reflected in many experimental cancer model systems, begging the question of whether certain biological aspects of cancer (eg. growth, evolution etc.) can ever be anticipated or if there remains an inherent unpredictability to cancer, similar to other complex biological systems. We demonstrate by a combination of agent-based mathematical modelling, analysis of patient-derived xenograft systems from multiple cancer types, and in-vitro culture that certain conditions may invoke chaotic fluctuations in the clonal landscape of cancer growth. Our findings indicate that under those conditions, the cancer genome may behave as a complex dynamic system, making its long-term evolution inherently unpredictable.

  Study EGAS00001007962

• Genomic Characterization CS-MATCH-0007 Arm Q

  The CS-MATCH-0007 protocol is part of a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing and RNA sequencing using pre-and post-treatment tumor biopsy specimens from patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to specific genomic alterations found in their cancers. Arm Q is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with HER2 amplification are treated with Kadcyla® (ado-trastuzumab emtansine). This subprotocol is one of the treatment arms included in the CS-MATCH-0007 protocol and will provide specimens for the program including tumor tissue and whole blood.

  Study phs001926

• International Cancer Proteogenome Consortium (ICPC): Proteogenomics of Early Stage Lung Adenocarcinoma in Taiwan

  Lung cancer in East Asia is characterized by a high percentage of never-smokers with early-onset adenocarcinoma, predominantly with EGFR mutations. To provide an insight into the molecular phenotype of this demographically distinct disease, we have performed a proteogenomics study on a prospectively collected cohort representing early stage lung adenocarcinoma in Taiwan. The distinct mutational profile revealed a high prevalence of the APOBEC mutational signature in early-onset females, implicating differential regulation of APOBEC enzymes and DNA damage pathways, as well as enrichment of mutational signatures congruent with environmental carcinogens over-represented in the genomic location of EGFR. We delineate the proteogenomic hallmarks of tumor progression and propose a proteomics-informed classification that resolves the EGFR mutation heterogeneity associated with survival within the early stages. Functional annotation of the molecular subtypes by protein network analysis highlights candidate biomarkers for patient stratification. Our integrative analysis reveals the molecular architecture of lung cancer in East Asia and enables the path for precision medicine.

  Study phs001954

• Investigation of BK Polyomavirus (BKPyV) and Molecular Signatures in UC specimens from Taiwan

  Urothelial carcinoma (UC) is the most prevalent cancer of kidney transplant recipients in some regions. The integration of BK polyomavirus (BKPyV) genome into the human genome is observed in some cases of UC. The prevalence of aristolochic acid (AA) mutational signatures in urothelial carcinoma is high in the general population of Taiwan. To better understand the mechanisms of UC carcinogenesis in kidney transplant recipients, 19 UC specimens were analyzed by whole genome sequencing (WGS) and Hybrid Sequencing.

  Study EGAS50000001063

• Cancer Discovery Hub (CDH), National Cancer Center Singapore

  This is a DAC for data deposited into EGA generated by Cancer Discover Hub, NCCS. The use of datasets in this portal is solely for research and academic use only, uses other than the have to be approved by the relevant DAC members.

  Dac EGAC50000000039

• Oncogenic and immunological targets for matched therapy of pediatric blood cancer patients: Dutch iTHER study experience

  Study EGAS00001008218

• B cell receptor silencing reveals origin and dependencies of high-grade B cell lymphomas with MYC and BCL2 rearrangements

  High-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) represent highly aggressive Germinal center (GC) derived B cell malignancies with dismal prognosis and limited therapeutic options. In the present study, we investigated the expression of BCR complex components, including immunoglobulin (IG) heavy (H) and light (L) chains, and CD79A and CD79B signaling subunits in HGBCL-DH-BCL2, scoring 65% of cases with undetectable IGH immunoreactivity (IGHUND). Transcriptomics (bulk RNA-seq) and genetic (whole exome/genome sequencing) analyses indicated that IGHUND and IGH+ HGBCL-DH-BCL2 lymphomas represent distinct biological entities. Specifically, IGHUND HGBCL-DH-BCL2 exhibit a GC DZ-like molecular program, and select subset-specific gene mutations pointing to distinct evolutionary trajectories respect to the IGH+ counterparts. IG profiling revealed that IGHUND HGBCL-DH-BCL2 preserved potentially productive, hypermutated IGH variable (V) gene rearrangements, indicating a selective advantage conferred to the malignant B cells by residual IGH molecules. Accordingly, disruption of the productively rearranged IGHG1 gene in BCRnull HGBCL-DH-BCL2 cell line model confirmed the dependency on IGH expression for optimal fitness. Using transcriptomics and in situ RNA-scope analysis, we reported that IGHUND HGBCL-DH-BCL2 originated from IG-class switched GC B cells, while IGH-expressing tumors were selected for continuous IGM expression. Moreover, while IGH+ HGBCL-DH-BCL2 favor IGM/IG-Kappa expression, IGHUND counterparts complete IG-Lambda light chain rearrangements. Notably, BCR silencing, caused by accelerated IGH turnover and reduced IGH expression, precedes HGBCL-DH-BCL2 onset, inducing RAG1/2-dependent IG light chain editing and eventually facilitating t(8;22)/IGL::MYC translocations. Finally, IGH silencing observed in HGBCL-DH-BCL2 cell models, which leads to intracellular retention/silencing of CD79B, results in reduced sensitivity to the CD79B-targeting antibody-drug conjugate Polatuzumab-vedotin. Collectively, HGBCL-DH-BCL2 originates from isotype-switched t(14;18)+ GC B cells that undergo IG light chain editing fuelling intra-clonal diversification, BCR silencing, and the acquisition of t(8;22) translocation, while preserving IGH dependency.

  Study EGAS50000001047

• Genomic determinants of response and resistance to inotuzumab in B-ALL

  Inotuzumab Ozogamicin (InO) is an antibody-drug conjugate which delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO treated B-cell acute lymphoblastic leukemia (B-ALL) patients, we sought to understand the genomic determinants of response to InO. Acquired CD22 mutations were observed in 11% (3/27) of post-InO relapsed samples. CD22 mutation types were diverse (frameshift, nonsense, missense and stoploss) and we identified multiple mechanisms of mutation induced CD22 escape, including protein truncation, protein destabilization, and epitope alteration. Accelerated acquisition of mutations by error-prone DNA damage repair could drive CD22 mutation and escape. Acquired loss-of-function mutations in TP53, ATM and CDKN2A were observed, suggesting compromise of the G1/S DNA damage checkpoint as a mechanism of evading InO-induced apoptosis. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. The diverse mechanisms of CD22 escape advocates for a refined approach for monitoring CD22-targeted therapy.

  Study EGAS50000000067

• Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q

  Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML.

  Study EGAS50000000743

• DHODH is a synthetic-lethal vulnerability in BCOR-deficient acute myeloid leukemia

  Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co- repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH’s role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.

  Study EGAS50000001108

• Somatic Mutation in Normal Bladder Study

  Adult human somatic tissues are landscapes of mutant clones, but little is known about how these landscapes are shaped by known cancer risk factors. The goal of this study was to determine how the main bladder cancer risk factors (sex and smoking) change the mutational landscape of the normal urothelium. We collected normal urothelium from 45 donors at autopsy by brushing ~2cm² of the surface epithelium in the upper part (dome) and lower part (trigone) of the bladder (79 samples total). To identify mutations with high sensitivity we employed ultradeep (~5000x) DNA error-correcting duplex-sequencing on a panel of 15 protein coding genes and the TERT promoter, previously described to be under positive selection in normal urothelium or relevant to bladder cancer. We identified thousands of clonal driver mutations, which demonstrate pervasive positive selection in the normal urothelium. Males showed a significantly higher number of driver truncating mutations in RBM10, CDKN1A and ARID1A, despite similar rates of non-coding mutations, indicating stronger positive selection and clonal expansion in the male urothelium. We also discovered clonal expansions driven by activating TERT promoter mutations in the normal bladder, which were strongly associated with age and smoking. These results demonstrate that sex and smoking shape the clonal landscape of the normal bladder and indicate that the high mutational content of normal tissues might be leveraged to study the effect of mutations in vivo (i.e. natural saturation mutagenesis). We will deposit in dbGaP de-identified relevant clinical information from the 45 donors and the fastq files derived from duplex sequencing of the 79 samples in the study. We will also deposit fastq files derived from duplex sequencing of 3 control cord blood samples.

  Study phs004105

• Epigenetic Control of Topoisomerase 1 by MacroH2A1.1

  DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for removing DNA supercoiling, aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic single-stranded DNA lesions (SSLs). What protects the genome from aberrant TOP1 activity remains unknown. Using a combination of CUT&RUN and TOP1 Covalent Adduct Detection (CAD) Seq in MDA-MB-231 breast cancer cells (American Type Culture Collection, ATCC), we identified chromatin context as an essential means to ensure TOP1cc resolution at TOP1 hot spots. Through its ability to bind poly(ADP-ribose) (PAR), a protein modification required for TOP1cc repair, the histone variant macroH2A1.1 establishes a TOP1-permissive chromatin environment, while the alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. MacroH2A1 isoform-specific analyses were based on reconstitution of macroH2A1.1 knockout cells with wild-type or PAR binding-deficient FLAG-tagged macroH2A1.1 in human breast cancer cells. Mechanistically, we find that macroH2A1.1 facilitates the recruitment of the TOP1cc repair factor XRCC1 in response to both endogenous and drug-induced topological stress. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect in breast and ovarian cancer cells. Consistent with this, low macroH2A1.1 expression correlated with improved survival in cancer patients treated with TOP1 inhibitors (TOP1i). We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.

  Study phs003729

• Genomic Characterization of Duke Melanoma Brain Metastases

  Previous work has shown that melanoma brain metastases (MBM) have a unique molecular profile compared to extracranial metastases (ECM). Description of the biology of MBM and associations between biological features and clinical outcomes will facilitate the design of rational therapies for patients with MBM. To better characterize the molecular profile of MBM, we conducted whole exome sequencing (WES) and total RNA sequencing on MBM tissues obtained from an independent cohort of 14 patients from Duke University Medical Center. This cohort adds valuable patient samples to the field and enables strengthened investigation of somatic mutations and gene expression profiles within and between cohorts. The mutational landscape and gene expression of MBM from the Duke cohort resembled those previously reported in a previously published dataset of WES and RNA sequencing in MBM and matched ECM tissues from UT MD Anderson Cancer Center (Fischer et al., 2019 30787016). Duke MBM demonstrated similar rates of mutations in genes associated with melanoma, including BRAF, NRAS, and PTEN, as the MD Anderson cohort. Immune populations in MBM were similar between Duke and MD Anderson MBM, though Duke samples demonstrated more resting CD4+ memory T cells. The ratio of M2 to M1 macrophages in the Duke cohort was similar to that of the MD Anderson cohort. In MBM, a higher M2:M1 ratio may contribute to an immune-suppressive tumor microenvironment. Sequencing data and sample attributes from MBM tissues obtained from 14 patients from Duke University Medical Center will be available through dbGaP.

  Study phs003009

• Nanopore whole-genome sequencing of human sarcomas

  We performed single and multi-region nanopore whole-genome sequencing on human sarcoma samples from adult and paediatric patients.

  Study EGAS50000000651

• Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer

  Immunotherapy has produced disappointing results in recurrent ovarian cancer (OC). However, the prognostic value of tumour-infiltrating lymphocytes (TILs) is largely based on the analysis of treatment-naive tumours. To understand the immunobiology of recurrent cancers, and their evolution, we profiled a total of 697 OC tumour samples (566 primary and 131 recurrent including 69 patient-matched samples) from 595 patients of five independent multi-institutional cohorts. By capturing heterogeneous TIL distributions, we identified four immune phenotypes associated with differential prognosis, TILs states and TILs:myeloid networks, which dictate malignant progression after chemotherapy and recurrence. Notably, recurrent tumours recapitulate the immunogenic landscapes of original cancers. Mirroring inflamed human OC, preclinical recurrent Brca1mut tumours maintained activated TILs:dendritic cells (DCs) niches but evaded immune control through COX/PGE2 signaling upregulation. Conversely, recurrent Brca1wt tumours displayed loss of TILs:DCs niches and accumulated immunosuppressive myeloid networks featuring Trem2/ApoEhigh TAMs and Nduf4l2high/Galectin3high malignant states. Our study highlights that persistent immunogenicity in recurrent OC is governed by the BRCA-dependent crosstalk between dissimilar myeloid cells and TILs. We propose new targets to modulate the malignant and TAM compartments which improve efficacy of standard of care chemotherapy in mouse OC models with HR deficiency.

  Study EGAS50000001069